Tumour immunology Flashcards
which cells attack tumours?
- CD8+ T cells
- Natural killer cells
how do t cells recognise infected or malignant cells
through major histocompatability complex molecules on antigen presenting cells
what are the three professional antigen presenting cells
- Dendritic cells (majority)
- Activated macrophages
- Activated B cells
give four features of MHC class 1
- Found on almost all nucleated cells (not onrbc or germline cells)
- Present endogenous antigens (intracellular, internal)
- Display self proteins, virus proteins, intracellular pathogens
- Present antigen to cytotoxic T cells (CD8)
give four features of class 2 MHCs
- Found primarily on Antigen presenting cells (APCs)
- Present exogenous antigens (extracellular, external)
- Phagocytosis, receptor mediate endocytosis
- Present antigen to helper T cells (CD4)
give four features of class 2 MHCs
- Found primarily on Antigen presenting cells (APCs)
- Present exogenous antigens (extracellular, external)
- Phagocytosis, receptor mediate endocytosis
- Present antigen to helper T cells (CD4)
what two signals are needed for t cells to be activated?
antigen
costimulation from an apc
what are the surface molecules and secreted molecules of CD4+ helper T cells
TCR, CD3, CD4 = surface molecules
IFNgamma, IL-2, IL-4, IL-5, IL-13, IL-10
what are the surface molecules and secreted molecules of CD8+ killer T cells?
TCR, CD3, CD8 = surface molecules
perforin, granzyme, IFN gamma
what are the functions of CD4 T cells?
- immunity against intracellular bacteria and parasites
- provide help to CD8 T cells
- promote humoral immune responses
what are the functions of CD8 T cells?
- when activated they become cytotoxic
- kill virally infected cells
- kill tumour cells
what combinations of signals allows NK cells to attack?
activating ligand but not MHC = attack
activating ligand + MHC = attack
How do NK cells make the decision to attack?
based on the balance of activating and inhibitory signals
describe the mechanism of perforin
When the NK cell approaches the target cell, secretory granules of perforin (&granzyme) accumulate towards it. Microtubules draw them towards the edge of the cell via secretory granule trafficking
Fusion of granules with the presynaptic membrane allows release of perforin (&granzyme)
Perforin then is able to polymerize and form a channel in the target cell membrane to enter the cell (needs Ca2+)
what needs to happen for a neoantigen to be made?
mutation needs to be generated, translated to protein, a peptide needs to be generated by the proteosome and pass into the ER. the peptide then needs to be bound by an MHC class 1 molecules.
what neoantigens can be recognised by T cells to initiate a response?
- mutated antigens
- overexpressed antigens
- germline antigens
- viral oncoproteins
what percentage of tumours are triggered by viruses?
about 15%
why are patients tissue more variable than using mice or cloned tumour cell lines?
- We use identical mice and only a few very in-bred mouse strains
- We use a few tumour cell lines, that are often extremely mutated after years in culture
- We inject at millions – the tumours grow within weeks rather than years like in real life
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what is one way of telling if T cells have an important anti-cance roles in patients?
what have the results shown us?
monitoring if patients on immunosuppressive therapies have an increased cancer risk
Some cancers increase in frequency if you are on immunosuppressive drugs
Risk sometimes disappears when they come off the immunosuppressant dugs and their t cells come back up again
transplant recipients on long temr immunosuppression have a greater risk of non-hodkinlymphoma and liver cancer possibly due to increased infection with some viruses
increased risk of lung and kidney cancers was also seen unconnected to infection
what are the four grades used to score immune cell infiltration (TIL) in human cancers
Grade 0 - no TIL
Grade 1- few
Grade 2 - moderate
Grade 3 - marked
how did the TIL grading correspond to survival rates?
grade 3 (with marked TIL) had 100% survival rate, the lower grades with fewer TIL had a worsening level or survival with the worst being Grade 0 with no TIL
how is the immunoscore determined?
take biopsy of tumour
section it and scan to look for T cells
the immune cells infiltrating the tumor are counted - those in the center of the tumour and at the invasive margin
both are important for outcome - no1 predicter of survival is whether you have T cells in the centre
what type of T cells give you a 5x chance of survival if they are present in the centre of your tumour
granzyme t cells
what t cells have a poor effect on prognosis?
Th2
Th17
Treg
what t cells have a good effect on prognosis?
CD8+
Th1
what is the main role and condition caused by Th1 cells
intracellular pathogens
chronic inflammation
what is the main role and condition caused by Th2 cells
extracellular parasites
allergic disorders
what is the main role and condition caused by Th17 cells
extracelluar pathogens
autoimmunity
what is the main role and condition caused by Th22
wound healing
inflammatory diseases
what is the main role of T reg cells
self tolerance
give examples of hot tumour types
melanoma, kidney, bladder, head and neck, non-small cell lung cancer
give examples of cold tumour types
most breast cancers, prostate, pancreatic, glioblastoma, ovarian